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Advanced Drug Delivery Reviews (v.59, #8)

Editorial Board (pp. ii).

Organelle-specific targeting in drug delivery and design by Carol S. Lim Theme Editor (pp. 697-697).

Targeted delivery to the nucleus by Colin W. Pouton; Kylie M. Wagstaff; Daniela M. Roth; Gregory W. Moseley; David A. Jans (pp. 698-717).

Macromolecules and supramolecular complexes are frequently required to enter and exit the nucleus during normal cell function, but access is restricted and exchange to and from the nucleus is tightly controlled. We describe the mechanisms which regulate nuclear import of endogenous molecules and indicate how viruses exploit these mechanisms during their life cycle. Opportunities exist to make use of natural pathways for delivery of therapeutic entities, in particular to develop safe and effective methods for gene therapy, although past attempts to design non-viral nuclear delivery systems have met with limited success. To increase the likelihood of success scientists will need an appreciation of the mechanisms by which viruses deliver their genomes to the nucleus, and will need a commitment to control the architecture of non-viral delivery systems at the molecular level. Effective delivery systems will require several attributes to facilitate endosomal escape, microtubular transport and uptake through the nuclear pore complex. The published literature provides a strong foundation for design of nuclear targeting systems. The challenge faced by delivery scientists is to assemble a system which is as effective as, for example, the adenovirus but which lacks its immunogenicity. This article reviews the relevant literature and indicates key areas for future research.

Keywords: Nuclear import; Nuclear pore complex; Importins; Intracellular trafficking; Microtubular trafficking; Dynein; Viral transport; Non-viral gene therapy; Gene delivery systems

Biodegradable nanoparticles for cytosolic delivery of therapeutics by Jaspreet K. Vasir; Vinod Labhasetwar (pp. 718-728).

Many therapeutics require efficient cytosolic delivery either because the receptors for those drugs are located in the cytosol or their site of action is an intracellular organelle that requires transport through the cytosolic compartment. To achieve efficient cytosolic delivery of therapeutics, different nanomaterials have been developed that consider the diverse physicochemical nature of therapeutics (macromolecule to small molecule; water soluble to water insoluble) and various membrane associated and intracellular barriers that these systems need to overcome to efficiently deliver and retain therapeutics in the cytoplasmic compartment. Our interest is in investigating PLGA and PLA-based nanoparticles for intracellular delivery of drugs and genes. The present review discusses the various aspects of our studies and emphasizes the need for understanding of the molecular mechanisms of intracellular trafficking of nanoparticles in order to develop an efficient cytosolic delivery system.

Keywords: Biodegradable polymers; Nanoparticles; Sustained release; Gene delivery; Drug delivery; Cellular uptake; Endocytosis

Delivery of drugs and macromolecules to mitochondria by Abhijit Mukhopadhyay; Henry Weiner (pp. 729-738).

Mitochondria is where the bulk of the cell's ATP is produced. Mutations occur to genes coding for members of the complexes involved in energy production. Some are a result of damages to nuclear coded genes and others to mitochondrial coded genes. This review describes approaches to bring small molecules, proteins and RNA/DNA into mitochondria. The purpose is to repair damaged genes as well as to interrupt mitochondrial function including energy production, oxygen radical formation and the apoptotic pathway.

Keywords: Abbreviations; mtDNA; mitochondrial DNA; PNA; peptide nucleic acid; TOM; translocase outer membrane; TIM; translocase inner membrane; TPP; triphenyl phosphonium ion; IMS; inter membrane space; VDAC; voltage dependent anionic channel; MERRF; myoclonic epilepsy and ragged-red fibres; NARP; neurogenic weakness, ataxia and retinitis pigmentosa; MELAS; mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; KSS; Kearns–Sayre syndrome; PEO; progressive external ophthalmoplegia.Mitochondrial DNA; Mitochondrial disease; Translocators; Protein and RNA import; Membrane insertion; Lipophilic cations

Drug delivery to peroxisomes: Employing unique trafficking mechanisms to target protein therapeutics by Stanley R. Terlecky; Jay I. Koepke (pp. 739-747).

Peroxisomes are multifunctional organelles of all human cells, responsible for a variety of essential biochemical and metabolic processes including α- and β-oxidation of specific fatty acids, plasmalogen biosynthesis and glyoxylate detoxification. Inborn errors of biogenesis or in the ability to synthesize or properly traffic specific enzymes to peroxisomes result in devastating human disease. The organelle has also emerged as a contributor to cellular oxidative stress through its ability to generate hydrogen peroxide. Unlike most other organelles, the peroxisome's import apparatus will accommodate fully folded, oligomeric and co-factor-bound substrates. The strategies outlined here are designed to take advantage of this unique mechanism to target protein therapeutics. Emphasis is also placed on how to deliver these bioactive molecules into cells to engage the peroxisomal protein import machine. The critical antioxidant enzyme catalase has been successfully delivered and targeted by many of the approaches detailed herein; these examples will be discussed.

Keywords: Abbreviations; AGT; Alanine:glyoxylate aminotransferase; CPP; Cell penetrating peptide; DAPI; 4′,6-diamidino-2-phenylindole; DHAP-AT; Dihydroxyacetone-phosphate acyltransferase; FlAsH; fluorescein arsenical hairpin binder; HA2; Hemagglutinin-2; HIV-TAT; Human immunodeficiency virus transactivator protein TAT; IRD; Infantile Refsum's disease; KANL; Lysine-alanine-asparagine-leucine; NALD; Neonatal adrenoleukodystrophy; NLS; Nuclear localization signal; PBD; Peroxisome biogenesis disorder; PH1; Primary hyperoxaluria type 1; PMP; Peroxisome membrane protein; PTS1 (or 2); Peroxisomal targeting signal type 1 (or 2); RCDP; Rhizomelic chondrodysplasia punctata; RING; Really interesting new gene; ROS; Reactive oxygen species; SKL; Serine-lysine-leucine; ZS; Zellweger syndrome.Aging; Biogenesis; Human peroxisomal disorders; Protein transduction; Reactive oxygen species; Targeting signals

Endocytic mechanisms for targeted drug delivery by Lisa M. Bareford; Peter W. Swaan (pp. 748-758).

Advances in the delivery of targeted drug systems have evolved to enable highly regulated site specific localization to subcellular organelles. Targeting therapeutics to individual intracellular compartments has resulted in benefits to therapies associated with these unique organelles. Endocytosis, a mechanism common to all cells in the body, internalizes macromolecules and retains them in transport vesicles which traffic along the endolysosomal scaffold. An array of vesicular internalization mechanisms exist, therefore understanding the key players specific to each pathway has allowed researchers to bioengineer macromolecular complexes for highly specialized delivery. Membrane specific receptors most frequently enter the cell through endocytosis following the binding of a high affinity ligand. High affinity ligands interact with membrane receptors, internalize in membrane bound vesicles, and traffic through cells in different manners to allow for accumulation in early endosomal fractions or lysosomally associated fractions. Although most drug delivery complexes aim to avoid lysosomal degradation, more recent studies have shown the clinical utility in directed protein delivery to this environment for the enzymatic release of therapeutics. Targeting nanomedicine complexes to the endolysosomal pathway has serious potential for improving drug delivery for the treatment of lysosomal storage diseases, cancer, and Alzheimer's disease. Although several issues remain for receptor specific targeting, current work is investigating a synthetic receptor approach for high affinity binding of targeted macromolecules.

Keywords: Lysosomes; Endosomes; Receptor mediated endocytosis; Clathrin; HPMA; Riboflavin

Visiting the ER: The endoplasmic reticulum as a target for therapeutics in traffic related diseases by Meir Aridor (pp. 759-781).

The endoplasmic reticulum (ER) is a central processor that controls the expression of functional proteins, required for the communication of the cell with the external environment. Plasma membranes receptors, ion channels, secreted hormones, catabolic and metabolic enzymes are folded and assembled in the ER. Key metabolic functions are also regulated from the ER. Molecular quality control monitors ER processing activities and co-ordinates these activities with cell and organism demands. Recent understandings of the molecular basis for ER processing activities illuminate the key role of the ER in the development of a variety of diseases. ER derived diseases include specific genetic disorders such as cystic fibrosis or highly prevalent diseases including diabetes and a range of neurodegenerative diseases. ER processing also plays a key role in the development of cancer. This review summarizes the molecular basis for ER processing functions and current avenues in ER-targeted drug development.

Keywords: COPII; Unfolded protein response (UPR); Traffic; Disease; Stress; Endoplasmic reticulum; Golgi; Degradation

Alternate routes for drug delivery to the cell interior: Pathways to the Golgi apparatus and endoplasmic reticulum by Maria Teresa Tarragó-Trani; Brian Storrie (pp. 782-797).

The targeted delivery of drugs to the cell interior can be accomplished by taking advantage of the various receptor-mediated endocytic pathways operating in a particular cell. Among these pathways, the retrograde trafficking pathway from endosomes to the Golgi apparatus, and endoplasmic reticulum is of special importance since it provides a route to deliver drugs bypassing the acid pH, hydrolytic environment of the lysosome. The existence of pathways for drug or antigen delivery to the endoplasmic reticulum and Golgi apparatus has been to a large extent an outcome of research on the trafficking of A/B type-bacterial or plant toxins such as Shiga toxin within the cell. The targeting properties of these toxins reside in their B subunit. In this article we present an overview of the multiplicity of pathways to deliver drugs intracellularly. We highlight the retrograde trafficking pathway illustrated by Shiga toxin and Shiga-like toxin, and the potential role of the B subunit of these toxins as carriers of drugs, antigens and imaging agents.

Keywords: Abbreviations; APC; antigen presenting cells; CT; Cholera toxin; CTL; cytotoxic T lymphocytes; DT; Diphtheria toxin; HLE; E. coli; heat labile toxin; ER; endoplasmic reticulum; ERAD; ER-associated protein degradation; GA; Golgi apparatus; Gb; ₃; globotriaosylceramide; GFP; green fluorescent protein; GM1; ganglioside GM1; IL-2; interleukin-2; M6PR; mannose-6-phosphate receptor; MHC; major histocompatibility complex; PE; Pseudomonas; exotoxin; ST; Shiga toxin; SLT; Shiga-like toxin; STB/SLTB; ST/SLT subunit B; SV40; simian virus 40; TAT; HIV-1 trans-activating transcriptional activator; T; _H; 1; helper T lymphocytes; TGN; trans-Golgi networkA/B toxins; Caveolae; Endoplasmic reticulum; Golgi apparatus; Lipid rafts; Lysosomes; Receptor-mediated endocytosis; Retrograde-trafficking pathway; Shiga/Shiga-like toxin; Targeted drug delivery

“Alternative” endocytic mechanisms exploited by pathogens: New avenues for therapeutic delivery? by L.K. Medina-Kauwe (pp. 798-809).

Some pathogens utilize unique routes to enter cells that may evade the intracellular barriers encountered by the typical clathrin-mediated endocytic pathway. Retrograde transport and caveolar uptake are among the better characterized pathways, as alternatives to clathrin-mediated endocytosis, that are known to facilitate entry of pathogens and potential delivery agents. Recent characterization of the trafficking mechanisms of prion proteins and certain bacteria may present new paradigms for strategizing improvements in therapeutic spread and retention of therapy. This review will provide an overview of such endocytic pathways, and discuss current and future possibilities in using these routes as a means to improve therapeutic delivery.

Intracellular trafficking of adenovirus: Many means to many ends by Philip L. Leopold; Ronald G. Crystal (pp. 810-821).

The intracellular trafficking of adenovirus capsids has been described mainly through observations of trafficking by capsids from subgroup C adenoviruses in transformed cell lines. The basic elements of the trafficking pathway include high affinity binding of the adenovirus capsid to receptors at the cell surface, internalization by endocytosis, lysis of the endosomal membrane resulting in escape to the cytosol, trafficking along microtubules, binding to the nuclear envelope, and insertion of the viral genome through the nuclear pore. The net effect of this basic pathway is to deliver the adenovirus genome to the nucleus in a highly efficient manner with greater than 80% of the genome reaching the nucleus in approximately 1 h. However, exceptions to this trafficking pattern have been noted, including: (1) variations based on adenovirus serotype; (2) variations based on target cell type; and (3) variations based on cell physiology. This review summarizes the classical adenovirus infection pathway along with the exceptions to that trafficking pathway, providing an overview of intracellular trafficking of adenovirus.

Keywords: Adenoviruses; Endocytosis; Intracellular trafficking; Viral receptors; Serum proteins; Cell physiology; Viral infection

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Advanced Drug Delivery Reviews (v.59, #8)